Advanced microfluidic capabilities will be developed to address a broad range of biochemical measurement problems that will benefit from precise and automated nano- to subnanoliter scale manipulations with high serial throughput capability. These devices will also lend themselves to massive parallel expansion leading to greater throughput possibilities for the generation of biochemical information. The focus of this work will be the development of microfabricated channel devices that can manipulate subnanoliter biochemical reaction volumes in a controlled manner so as to produce experimental results at rates of 1-10 Hz per channel. These reaction volumes will be capable of containing molecular or particulate species without diffusive losses. The occupation number of particulate species in these reaction volumes, e.g., biological cells or combinatorial library beads, will be controllable from single to multiple entities. Thus, highly automated single cell investigations will be possible with these devices as well as ensemble studies, i.e., the response from a collection of cells. The individual reaction volumes will be manipulated in serial fashion, in much the same way as a digital shift register, allowing unique identification of each reaction "cell" throughout an experiment. These reaction volume shift register devices will be integrated with capabilities to add reagents to individual reaction volumes at "reagent stations" and subsequently extract material for analysis at "assay stations." Direct assay of reaction volumes by optical means will also be possible. Development of the proposed capabilities will enable the ability to perform a number of different types of high throughput experiments (105-106/day) using single microfluidic devices driven by PC computer size hardware. Proportionately greater throughput can be achieved by parallelization with minimally increased hardware demands. This technology will have application to problems such as screening molecular or cellular targets using single beads from split/pool combinatorial libraries, screening single cells for RNA or protein expression, genetic diagnostic screening at the single cell level or performing single cell signal transduction studies.